Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity

Simon McGrath reports on Dr Snell's new study demonstrating that ME/CFS patients have a reduced capacity to exercise when they repeat a maximum exercise test one day on - unlike healthy controls.

One of the biggest problems of getting ME/CFS taken seriously is that often we 'look' normal, even though we feel lousy, and most lab tests produce 'normal' findings. How do we prove to the world that we are sick?

A defining feature of ME/CFS is Post-Exertional Malaise (PEM) and a couple of studies have clearly demonstrated PEM in patients [see box]. However, PEM is a subjective experience and one that can only be measured by patient self-report, which won't satisfy everyone.

Dr Chris Snell, Staci Stevens, Dr Todd Davenport, and Dr Mark VanNess's new study aimed to objectively demonstrate the problem of post-exertional malaise, by using a repeat Cardiopulmonary Exercise Test (CPET). As they formally hypothesized in their paper: "an exacerbation of symptoms following the first test would be reflected in physiological responses to the second".

The study

The 51 CFS patients were all women, met Fukuda criteria and also reported PEM. Controls, also female, were similar in age and BMI, and were fairly sedentary. In fact, the results of the first CPET revealed that the controls were in the bottom 10% of published population norms and would count as deconditioned. CFS patients were barely different from controls so were also deconditioned, but, crucially, they were ill while controls were healthy, casting doubt on the idea that deconditioning is responsible for CFS.

CPET: Cardiopulmonary Exercise Testing explained

CPET is the Gold standard for measuring physical capacity, used by athletes wanting to measure the effectiveness of their training programs. It's also used medically e.g. to diagnose cardiovascular, breathing and muscle disorders.

The principle is to get someone to exercise to exhaustion, using a protocol that starts easy and gets increasingly difficult until the subject can do no more. The key measures for this study are the Volume of Oxygen consumed (VO2) and the amount of work done, measured in Watts on the exercise bike.

Anaerobic/Ventilatory Threshold

A critical factor is the anaerobic threshold, the point at which the body has to supplement normal aerobic (oxygen-burning) metabolism with much less efficient anaerobic metabolism, creating lactic acid. This threshold is measured in CPET by finding the point where carbon dioxide (CO2) starts to be produced faster than Oxygen, and is called the Ventilatory Threshold, or VT (strictly, VO2 VT).

VO2 max versus VO2 peak

One challenge of CPET is detecting if the person is using maximal effort, as opposed to trying pretty hard. Data showed that CFS patients and subjects here all went deep into anaerobic exercise and met at least one other measure of high effort. However, as it's almost impossible to be completely sure, the study reported 'peak' measures instead of maximum, e.g. VO2 peak, not VO2 max.

Note there are equivalent thresholds for work output, in watts: W max, W peak and W VT

The big differences between the groups emerged on the second maximal CPET test, 24 hours after the first. On average, controls did slightly better on Day 2 (something that has been observed in other studies too) while patients did substantially worse. Interestingly, VO2 peak did not differ significantly between patients and controls, but peak Watts output was significantly lower, as was VTO2 . The biggest difference of all was for Watts output at VT, down for the patient group by over half.

The study found the repeat test could separate CFS patients from controls in this sample with 95% accuracy (3 errors in total). They also used a statistical technique called 'cross-validation', which indicated the test would achieve a 90% accuracy in an independent sample (though see issue with convenience sample below).

This ability of a 2-day repeat test to discriminate healthy but sedentary controls from CFS patients is critical. In theory, doctors can manage this easily enough without a CPET test. However, where there is doubt about the reality of symptoms, as can happen with disability insurance claims, an objective test can demonstrate that a patient really is sick. As Workwell Foundation notes, it's useful in legal or medical disputes; the reduced performance on VT is "impossible to fake", adds Dr Snell.

The study conclusion said:

the post-exertional state in CFS is characterized by objectively measurable deficits in submaximal metabolism and workload that would be nearly impossible for patients to fabricate

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In some ways the findings are unexpected, as it was the same group's earlier finding of a substantial drop in VO2 max on the second test that caused such a buzz amongst patients. And the big drop in output at VT wasn't seen in a study (albeit a small one) by a separate research group, though a smaller drop was seen for VT, and VO2 max in a study presented at an IACFS conference. I asked Chris Snell if he was surprised by the finding. "No", came the reply: the initial study was small making the findings less robust, and he said that a much bigger effect on VT than VO2 max has been seen in the clinic too.

Evidence of Post-Exertional Malaise from subjective studies​

As well as the objective evidence from this new paper, PEM has been shown by self-report measures too. A 2010 study from Pacific Fatigue Labs found that only 1 of 25 female CFS patients recovered from a maximal exercise test 48 hours later while all 23 sedentary controls did. Another study using a moderate exercise test found that fatigue and pain increased in the 48 hours after exercise in CFS patients - while it returned to normal in that time for both healthy controls and Multiple Sclerosis patients.​

Committed to Maximal CPET

Given that it's hard enough for people with ME/CFS to do one maximal test, let alone two, these results create the temptation to just run the second test as far as the Ventilatory Threshold and forget about VO2 max. But Chris Snell stressed that the Workwell Foundation remains committed to the repeat-maximal approach. First, VT can't be measured on the fly so they wouldn't know when to stop the test. And perhaps more importantly, the post-exertional effect appears to differ by patient, with some showing a greater effect on peak measures and others at VT. Dr Snell suggested that varying post-exertional responses may well reflect different underlying pathologies.

Unique to ME/CFS?

Is this the killer test that uniquely identifies CFS patients? Dr Snell has reported that their clinic has tested patients with numerous illnesses including Multiple Sclerosis and Congestive heart failure, but have only seen the problem in ME/CFS patients. Published studies show normal repeat CPET performance for sarcoidosis, angina, Chronic Airflow Obstruction, Pulmonary Hypertension and heart disease. I’ve seen no studies showing failure to reproduce CPET results in other illnesses, but it’s probably too soon to say if this is unique to ME/CFS, or just very unusual.

What might cause the exercise problems?

The authors suggest that a synergy of small effects across multiple systems could be responsible for the poor exercise performance of the individuals with CFS. Lower oxygen carrying capacity could result from low blood volume, while low oxygen consumption could also result from autonomic dysfunction and reduced ventilation. But research into the causes is needed.

No study is perfect...

There were only 10 controls, though as the repeatability of CPET results is firmly established (with 94% reliability between tests), in some ways controls mainly serve to demonstrate that the protocol and equipment is working properly.

The CFS patients were a convenience sample, rather than, for example, consecutive referrals to a secondary clinic. This, and the fact that patients had agreed to a repeat maximal exercise test, means the results might not generalize to the patient population as a whole.

The earlier study by this group, and the other studes from independent groups, didn't find the dramatic changes with workload at the ventilatory threshold, so further replication would help to confirm the nature of the changes.

These findings, which make visible the hallmark ME/CFS problem of post-exertional malaise, have potentially huge importance. Replication of this study, perhaps with a more representative sample of CFS patients and some sick controls, should in my view be a priority for the research community. Stage two of the huge CDC multi-clinic study could provide the perfect opportunity for this.

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This is a start!!! Albeit not one any of us were expecting, but woohoo!! It really is a start, and if they can identify sub groups, and then correlate with the subgroups, we could very well get confirmatory results, and testing, and legalities tied down, and finally, some type of healthcare, oh...and the very least, a howdy doo.

Thank you Simon for your clear presentation of this study. It is apparent that this two day test can be beneficial for those who are building a case for the diagnosis of me/cfs but, does this mean that if one does not show a positive outcome of this test, that they do not qualify for a diagnosis of me/cfs. Does this back up the need of the ccc or Icc criteria having the mandatory symptom of pem/pene?

I have a concern, though, about its wide use as a diagnostic tool and that's whether the test itself could provoke a relapse. Do the authors have anything to say about this in their paper, or any follow-up data?

Thank you Simon for your clear presentation of this study. It is apparent that this two day test can be beneficial for those who are building a case for the diagnosis of me/cfs but, does this mean that if one does not show a positive outcome of this test, that they do not qualify for a diagnosis of me/cfs. Does this back up the need of the ccc or Icc criteria having the mandatory symptom of pem/pene?

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Thanks!

The results of this study showed that it should detect 90% of CFS cases, or 10% of Fukuda-defined CFS cases would be missed. They didn't assess patients according to other criteria so it doesn't say anything about CCC and ICC - both of these require self-reported symptoms eg post-exertional malaise, rather than objective markers of exercise dysfunction. It would have been interesting to see follow-up symptomatic data for this study, as well as the objective data, to see how well the two correlated.

I have a concern, though, about its wide use as a diagnostic tool and that's whether the test itself could provoke a relapse. Do the authors have anything to say about this in their paper, or any follow-up data?

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That's a very important point, and no, it wasn't addressed in the paper. A number of people who have undertaken the test have reported they recovered without any permanent deterioration, including Lannie and Jennie Spotilla, but I do think that if the test is to be widely used there needs to be systemmatic data on the likely impact on patients, both post-exertional symptoms and any relapses.

I think the repeat exercise testing is some of the most important research that has ever appeared into ME. Until we have something better I think this should be considered the Gold Standard in ME functionality testing, although I do thing we need studies showing it works in CCC and ICC defined cases to address possible criticism.

This does exclude more severe patients though. If this research can be advanced and other markers found as a result, then testing on bedbound patients might become possible ... but for now it isn't.

"The authors suggest that a synergy of small effects across multiple systems could be responsible for the poor exercise performance of the individuals with CFS." I think this statement is critical. Its looking increasingly likely that well defined CFS is a heterogenous collection of different problems. Traditional medicine has looked at single-cause disease. For a heart to not supply sufficient blood for everyday use, for example, it must have seriously degraded capacity. I have been asking a question for some years now: what happens if you lose much less capacity, say 10 to 20% in many interacting systems? Rather than failure at one critical point, its the entire system that would be degraded, and testing each individual part would show up as normal.

Consider a chain of things A to D. (This could be mitochondria, muscle function, heart function, circulation function for example.) Now suppose heart function is down 60%, then the circulation output would be down 60% as its on the critical path. Consider however if all of them were down by just 20% each, which might not be considered normal. What is the outcome? (0.8)^4 = approx 41% capacity. This is almost the same as a 60% fall in heart function, if measured over the entire chain of mechanisms.

Could you clarify for foggy brains what VO2 is, please? I know that VT02 is the ventilatory threshold, but VO2?

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Sorry, thought I'd explained CPET well, but omitted the most important bit of info (would like to blame my illness for this but don't think that's the case).

VO2 is Volume of Oygen consumed.
VO2 plain and simple is measured in litres, but as VO2 depends so much on a person's size, it's usually expressed as mls O2, per minute, per kilo of body mass. For example, in this study the VO2 peak (volume of oxugen consumed) was 21.5 ml O2/min/kig - which is very low.

So VO2 max, VO2 peak and VTO2 are all volume of oxygen consumed per minute per kilo of body mass, at maximum, peak and ventilatory threshold. VTO2 is probably better called VO2 VT, but VTO2 is often used instead.

It would be interesting to do immune system testing at the same time prior to tests, after first test, after second test and after different recovery times.

Also I was wondering how this fits in with Julia Newtons work looking at lactic acid in muscle tissue. I was thinking this may relate to the VT02 threshold

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I think the former is being done by Nancy Klimas, though I suspect she only uses a single maximal test. As Sasha notes the Lights looked at immune markers - or rather mRNA of immune marker proteins and found a small difference in CFS for the CD4 protein mRNA. They used a single 'moderate' exercise protocol, rather than a maximal one (though was probably close to maximal for the most severely affected patients they used,and these patients accounted for most of the effect seen).

Interesting idea about Julia Newton's lactic acid test, though her group didn't use a maximal test, and didn't use a repeat test either. The Snell study here didn't find a difference in VT for the first test, only on the repeated test.

Having been ill for nearly 11years, it can now take up to a week before PEM hits me. It laso lasts for a lot longer (for the same amount of overdoing) than it did earlier on.
I'm not sure testing just one day after (on myself) would actually show anything (apart from reaching the lactic acid thing far too soon and not being able to get into aerobic metabolism at all, which is what shows on the first testing anyway.)

I would be really interested in seeing exercise testing done even later - and then some more to see how long it lasts for.
And to have that related to the length of time the subject has beeen ill.

I don't think I'm the only person who has found this peculiarity.

Thank-you, Simon for reporting this great bit of research.
It really is incredibly hopeful to, finally, see the right things being looked for and tested.

I wish I could be tested. In the cold below 12 deg C I can repeat more or less the same test again and again for a couple of weeks, and do similar average miles for average heart rates, in fact I can see gains in mileage and lower heart rates.

Simon. Another cracker and very nicely presented on the full version I must say. Loved the cartoon

I couldn't get my head round this paper so thank you for persevering. Kind of what makes this place so great. If I can't figure it out then chances are someone else can

Having just returned from hospital and spoken with some physiologist science boffin about my 'mass of data' it would appear that initial suggestions are that my poor brain cell is being starved of oxygen during the night. It's too soon to say 'apnea' but we talked a bit around the topic; and I am left wondering to what degree oxygen starvation generally could be responsible for my muscle problems also (and lack of energy too I suppose) during the night and during the day.

It seems that oxygen is tied up with much that might be wrong. If my cells are not getting the oxygen they need then, as you said above, the outcome is more lactic acid and pain and discomfort for me. An inability to operate my muscles or for my muscles to recover from exertion. But above looks at inability to recover from exercise; and not ability to exercise in the first place - I am wondering then if those controls were experiencing the degree of muscle pain and ache etc. that I do constantly. Maybe this is where Prof. Newton's work comes into focus. Are 'we' just not getting enough oxygen, or not processing it, or not being able to process it?

VO2 is Volume of Oygen consumed.
VO2 plain and simple is measured in litres, but as VO2 depends so much on a person's size, it's usually expressed as mls O2, per minute, per kilo of body mass. For example, in this study the VO2 peak (volume of oxugen consumed) was 21.5 ml O2/min/kig - which is very low.

So VO2 max, VO2 peak and VTO2 are all volume of oxygen consumed per minute per kilo of body mass, at maximum, peak and ventilatory threshold. VTO2 is probably better called VO2 VT, but VTO2 is often used instead.

Having been ill for nearly 11years, it can now take up to a week before PEM hits me. It laso lasts for a lot longer (for the same amount of overdoing) than it did earlier on.
I'm not sure testing just one day after (on myself) would actually show anything (apart from reaching the lactic acid thing far too soon and not being able to get into aerobic metabolism at all, which is what shows on the first testing anyway.)

I would be really interested in seeing exercise testing done even later - and then some more to see how long it lasts for.
And to have that related to the length of time the subject has beeen ill.

I don't think I'm the only person who has found this peculiarity.

Thank-you, Simon for reporting this great bit of research.
It really is incredibly hopeful to, finally, see the right things being looked for and tested.

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I find that PEM takes longer to appear when I am relatively well, and at best it becomes almost imperceptible. Before I started getting these improved phases, my PEM occurred 2 days after exertion, almost like clockwork.

The fact that further exertion seems to put the PEM on hold, and that it then comes back with a vengeance, makes me extremely curious to know what is happening physiologically.

Having been ill for nearly 11years, it can now take up to a week before PEM hits me. It laso lasts for a lot longer (for the same amount of overdoing) than it did earlier on.
I'm not sure testing just one day after (on myself) would actually show anything (apart from reaching the lactic acid thing far too soon and not being able to get into aerobic metabolism at all, which is what shows on the first testing anyway.)

I would be really interested in seeing exercise testing done even later - and then some more to see how long it lasts for.And to have that related to the length of time the subject has beeen ill.

I find that PEM takes longer to appear when I am relatively well, and at best it becomes almost imperceptible. Before I started getting these improved phases, my PEM occurred 2 days after exertion, almost like clockwork.

The fact that further exertion seems to put the PEM on hold, and that it then comes back with a vengeance, makes me extremely curious to know what is happening physiologically.

Answers to such questions could be invaluable.

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Interesting point about the variability in PEM: mine doesn't even wait for 24 hours before it hits but clearly for others, including yourselves, it takes much longer, and that could complicate things.

Without changing their setup much, it would be interesting to ask patients how long before their PEM typically occurs, and correlate that with changes seen between test 1 & 2. They already have illness duration data, so could include that in the analysis too. (I don't know if they have looked at that separately).